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Signals From the Embryonic Mouse Pancreas Induce Differentiation of Human Embryonic Stem Cells Into Insulin-Producing ß-Cell–Like Cells

¹ Division of Developmental Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden
² Cellartis, Gothenburg, Sweden

The recent success in restoring normoglycemia in type 1 diabetes by islet cell transplantation indicates that cell replacement therapy of this severe disease is achievable. However, the severe lack of donor islets has increased the demand for alternative sources of ß-cells, such as adult and embryonic stem cells. Here, we investigate the potential of human embryonic stem cells (hESCs) to differentiate into ß-cells. Spontaneous differentiation of hESCs under two-dimensional growth conditions resulted in differentiation of Pdx1⁺/Foxa2⁺ pancreatic progenitors and Pdx1⁺/Isl1⁺ endocrine progenitors but no insulin-producing cells. However, cotransplantation of differentiated hESCs with the dorsal pancreas, but not with the liver or telencephalon, from mouse embryos resulted in differentiation of ß-cell–like cell clusters. Comparative analysis of the basic characteristics of hESC-derived insulin⁺ cell clusters with human adult islets demonstrated that the insulin⁺ cells share important features with normal ß-cells, such as synthesis (proinsulin) and processing (C-peptide) of insulin and nuclear localization of key ß-cell transcription factors, including Foxa2, Pdx1, and Isl1.

Abbreviations: DAPI, 6'diamidino-2-phenylindole; dhESC, differentiated human embryonic stem cell; EGFP, enhanced green fluorescent protein; hESC, human embryonic stem cell; mAb, monoclonal antibody; MEF, mouse embryonic fibroblast; PFA, paraformaldehyde; PBS-T, Triton X-100 in PBS

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